• Molecules and Cells
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• 제28권6호
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• pp.501-507
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• 2009

Fragile X syndrome (FXS) is caused by a lack of the fragile X mental retardation protein (FMRP) due to silencing of the Fmr1 gene. As an RNA binding protein, FMRP is thought to contribute to synaptic plasticity by regulating plasticity-related protein synthesis and other signaling pathways. Previous studies have mostly focused on the roles of FMRP within the hippocampus - a key structure for spatial memory. However, recent studies indicate that FMRP may have a more general contribution to brain functions, including synaptic plasticity and modulation within the prefrontal cortex. In this brief review, we will focus on recent studies reported in the prefrontal cortex, including the anterior cingulate cortex (ACC). We hypothesize that alterations in ACC-related plasticity and synaptic modulation may contribute to various forms of cognitive deficits associated with FXS.

• Biomolecules & Therapeutics
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• 제25권3호
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• pp.231-238
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• 2017

Myelin is a specialized structure of the nervous system that both enhances electrical conductance and insulates neurons from external risk factors. In the central nervous system, polarized oligodendrocytes form myelin by wrapping processes in a spiral pattern around neuronal axons through myelin-related gene regulation. Since these events occur at a distance from the cell body, post-transcriptional control of gene expression has strategic advantage to fine-tune the overall regulation of protein contents in situ. Therefore, many research interests have been focused to identify RNA binding proteins and their regulatory mechanism in myelinating compartments. Fragile X mental retardation protein (FMRP) is one such RNA binding protein, regulating its target expression by translational control. Although the majority of works on FMRP have been performed in neurons, it is also found in the developing or mature glial cells including oligodendrocytes, where its function is not well understood. Here, we will review evidences suggesting abnormal translational regulation of myelin proteins with accompanying white matter problem and neurological deficits in fragile X syndrome, which can have wider mechanistic and pathological implication in many other neurological and psychiatric disorders.

• Molecules and Cells
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• 제43권10호
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• pp.870-879
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• 2020

Dendrites require precise and timely delivery of protein substrates to distal areas to ensure the correct morphology and function of neurons. Many of these protein substrates are supplied in the form of ribonucleoprotein (RNP) complex consisting of RNA-binding proteins (RBPs) and mRNAs, which are subsequently translated in distal dendritic areas. It remains elusive, however, whether key RBPs supply mRNA according to local demands individually or in a coordinated manner. In this study, we investigated how Drosophila sensory neurons respond to the dysregulation of a disease-associated RBP, Ataxin-2 (ATX2), which leads to dendritic defects. We found that ATX2 plays a crucial role in spacing dendritic branches for the optimal dendritic receptive fields in Drosophila class IV dendritic arborization (C4da) neurons, where both expression level and subcellular location of ATX2 contribute significantly to this effect. We showed that translational upregulation through the expression of eukaryotic translation initiation factor 4E (eIF4E) further enhanced the ATX2-induced dendritic phenotypes. Additionally, we found that the expression level of another disease-associated RBP, fragile X mental retardation protein (FMRP), decreased in both cell bodies and dendrites when neurons were faced with aberrant upregulation of ATX2. Finally, we revealed that the PAM2 motif of ATX2, which mediates its interaction with poly(A)-binding protein (PABP), is potentially necessary for the decrease of FMRP in certain neuronal stress conditions. Collectively, our data suggest that dysregulation of RBPs triggers a compensatory regulation of other functionally-overlapping RBPs to minimize RBP dysregulation-associated aberrations that hinder neuronal homeostasis in dendrites.

• BMB Reports
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• 제52권5호
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• pp.304-311
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• 2019

The cytoplasmic FMR1-interacting protein family (CYFIP1 and CYFIP2) are evolutionarily conserved proteins originally identified as binding partners of the fragile X mental retardation protein (FMRP), a messenger RNA (mRNA)-binding protein whose loss causes the fragile X syndrome. Moreover, CYFIP is a key component of the heteropentameric WAVE regulatory complex (WRC), a critical regulator of neuronal actin dynamics. Therefore, CYFIP may play key roles in regulating both mRNA translation and actin polymerization, which are critically involved in proper neuronal development and function. Nevertheless, compared to CYFIP1, neuronal function and dysfunction of CYFIP2 remain largely unknown, possibly due to the relatively less well established association between CYFIP2 and brain disorders. Despite high amino acid sequence homology between CYFIP1 and CYFIP2, several in vitro and animal model studies have suggested that CYFIP2 has some unique neuronal functions distinct from those of CYFIP1. Furthermore, recent whole-exome sequencing studies identified de novo hot spot variants of CYFIP2 in patients with early infantile epileptic encephalopathy (EIEE), clearly implicating CYFIP2 dysfunction in neurological disorders. In this review, we highlight these recent investigations into the neuronal function and dysfunction of CYFIP2, and also discuss several key questions remaining about this intriguing neuronal protein.

• 한국가금학회지
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• 제48권2호
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• pp.81-90
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• 2021

조류 인플루엔자 바이러스는 다양한 숙주 단백질을 이용해야만 증식이 가능하다. 포유류 (사람, 쥐) Fragile X mental retardation protein (FMRP)는 최근 인플루엔자 A 바이러스 viral RNP (vRNP)의 조립을 돕고, 이를 핵에서 세포질로 운반시켜 바이러스 증식에 도움을 준다. 하지만, 조류 인플루엔자 바이러스의 주요 숙주인 닭에서는 FMRP translational regulator 1 (FMR1) 유전자의 기능이 규명되지 않았다. 본 연구는 CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats/Cas9) 유전자 가위를 이용해 정확히 닭 FMR1 유전자를 제거하여 닭 FMR1 유전자가 조류 인플루엔자 바이러스 증식에 어떤 영향을 끼치는지 연구하였다. 닭 FMR1 유전자는 닭 배아섬유아세포 (DF1세포)에서 초기 조류 인플루엔자 바이러스의 유전자 발현을 촉진하나, 감염 후 24시간 뒤에는 바이러스 생산 및 바이러스 중합효소 (Polymerase)의 활성에 영향을 끼치지 않았다. 또한, 야생형 닭 FMR1 유전자를 과발현 함에도 불구하고, 조류 인플루엔자 바이러스의 생산량에는 변화가 없었다. 위 결과들은 닭 FMR1은 포유류 FMR1 유전자에 비해 조류 인플루엔자 바이러스의 증식에 큰 영향을 주지 못하는 숙주인자임을 시사한다. 또한, 닭 FMR1처럼 기존에 포유류에서 알려진 숙주 인자를 목표로 하는 조류 인플루엔자 바이러스 저항성 치료제 및 형질전환 동물을 생산할 때, 조류 시스템에서 위 숙주 인자의 기능이 보존돼 있는지 고찰할 필요가 있다고 사료된다.